U.S. Pat. No. 6,825,188 B2 to Callahan et al., which is hereby incorporated by reference in its entirety, describes compounds of Formula (I) with a benzazepine core structure, process for preparing and methods for using the aforementioned compounds in the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis.
One of the processes described in the U.S. Pat. No. 6,825,188 B2 to Callahan et al., which is hereby incorporated by reference in its entirety, utilizes an N-oxide protected pyridine intermediate in the synthesis of the benzazepine core compounds disclosed therein.
A retrosynthetic analysis of the synthesis of compounds described in the U.S. Pat. No. 6,825,188 B2 to Callahan et al., which is hereby incorporated by reference in its entirety, is discussed below.
In particular, a retrosynthetic analysis shown below for preparing compound 1 in Scheme 1 reveals a disconnection that gives previously prepared (±, S or R)-Methyl 2,3,4,5-tetrahydro-8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-1H-2-benzazepine-4-acetate (also known as Methyl (±,4R or 4S)-2,3,4,5-tetrahydro-8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-1H-2-benzazepine-4-acetate (CA-style name)), 2 (see, Wallace, M. D.; McGuire, M. A.; Yu, M. S.; Goldfinger, L.; Liu, L.; Dai, W.; Shilcrat, S. Organic Process Research and Development 2004, 8, 738, which is hereby incorporated in reference in its entirety) and pyridyl sidechain 3.
Compound 1 as shown in Scheme 1 represents each of the following compounds: (±)-3-oxo-8-{[3-(pyridin-2-ylamino)propyl]oxy}-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid, (S)-3-oxo-8-{[3-(pyridin-2-ylamino)propyl]oxy}-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid, (R)-3-oxo-8-{[3-(pyridin-2-ylamino)propyl]oxy}-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid, or a pharmaceutically acceptable salt thereof. However, one of skill in the art would expect that conversion of the alcohol of 3 into a leaving group results in rapid and temperature-dependent cyclization (vide infra) to give 4, which does not act as an electrophile. The acidity of the solution would then dictate the dominant species, 4a or freebase 4b.
The first generation synthesis of Compound 1 shown in Scheme 2 (as disclosed in U.S. Pat. No. 6,825,188 B2 to Callahan et al., which is hereby incorporated by reference in its entirety), relied on the aforementioned retrosynthetic analysis disconnection. In particular, Scheme 2, shows the synthesis scheme as represented by one of the isomers of Compound 1: i.e., (S)-3-oxo-8-{[3-(pyridin-2-ylamino)propyl]oxy}-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid,

To circumvent decomposition issues of compound 3 to compound 4 as described above in Scheme 1, the pyridine lone pair was protected as the N-oxide in compound 5. This was accomplished by use of expensive, but commercially available 2-chloropyridine N-oxide Compound 5. The chloride of 5 was first displaced with an amine to generate 6. Treatment with thionyl bromide provided the alkylating agent 7 which was stable and isolable. The phenol 2 was alkylated under basic conditions using 7 which gave 8. Zinc dust removal of the N-oxide to give 9 proved difficult-to-scale due to the density of zinc dust. Issues with adequate mixing gave variable results and differed with reactor configuration. The active principle ingredient (1) could be generated, though, by saponification of methyl ester 9 (48% overall yield from 2).
Three major issues were found in the use of this route: 1) expensive 2-chloro-N-oxide (“N-oxide”) (5) is supplied as an aqueous solution and requires a lengthy azeotropic distillation before use; 2) Zn dust reduction of the N-oxide is unpredictable, 3) the N-oxide intermediates are thermally unstable.
In searching for alternative synthetic processes, it was thought that use of a borane protecting group instead of the N-oxide, would provide a viable alternative in light of literature precedents that illustrate the strength of the borane-heterocycle bond.
For instance, the nitrogen lone pair of an oxazole forms surprisingly stable oxazole-borane complexes which requires acidic or Pd treatment for removal. (i.e., see, Monahan, S. D.; Vedejs, E. J. Org. Chem., 1996, 61, 5192 and Zajac, M. A.; Vedejs, E. Org. Lett., 2001, 3, 2451). These complexes are completely stable to chromatography, air and moisture. Additionally, 4-dimethylaminopyridine (DMAP) forms a complex with borane quickly and quantitatively and exhibits similar stability when compared to oxazole-borane complexes (Shapland, P.; Vedejs, E. J. Org. Chem., 2006, 71, 6666.).
Based on the aforementioned examples, it was thought that specific pyridine intermediates used in the synthesis of benzazepine core structure compounds, such as those described in U.S. Pat. No. 6,825,188 B2 to Callahan et al., which is hereby incorporated by reference in its entirety, would exhibit or behave similarly to form stable borane complexes.
However, in considering alternative synthetic routes, while no literature examples were found describing use of borane as a protecting group, there were additional concerns that such a borane protected intermediate would survive extreme reaction conditions, such as treatment with K2CO3 and heat.
Thus, although the processes disclosed in U.S. Pat. No. 6,825,188 B2 to Callahan et al., which is hereby incorporated by reference in its entirety, produces benzodiazepinyl core structure compounds as defined therein, there is a need to improve processes and find alternative processes for the preparation of such benzodiazepinyl core structure compounds, in light of aforementioned problems associated with the N-oxide protection as discussed above.
It has now been found that benzazepine compounds as discussed herein can be prepared with the use of a borane protecting group with the pyridine starting material, instead of using an N-oxide protecting group with the pyridine starting group to produce such benzazepine compounds efficiently in high yield and high purity. The efficiency of this process and the quality and yield of the benzazepine product compounds are particularly important when preparing said product on a large scale for therapeutic use.
The present invention is directed to overcoming these and other problems encountered in the art.